Papillary muscles. Dark side of the heart: A simple approach for a forgotten structure.

PURPOSE: Transthoracic echocardiography (TTE) is currently the election method for initial screening of left ventricular papillary muscles (PM). However, diagnosis of borderline PM hypertrophy with TTE is not always feasible due to cumbersome interpretation of different PM diameters and the absence of precise normal ranges in the literature. The objective of this study was to obtain TTE normal cutoff values and to describe convenient indexes of PM dimensions. METHODS: Healthy volunteers with normal electrocardiogram were included for TTE assessment. Vertical (Vd) and horizontal (Hd) PM diameters were measured to obtain maximum diameter (Md) and areas of the anterolateral PM (APM) and posteromedial PM (PPM) to obtain PM total area (PMTA). RESULTS: A total of 82 patients were screened, and 6 (7.3%) with bifid PM were excluded from analysis. APM and PPM had similar Vd (APM: 8.3 ± 1.2, PPM: 7.9 ± 1.1 mm2 , P = NS) and Hd (APM: 8.2 ± 1.3, PPM: 8.3 ± 1.2 mm2 , P = NS). Finally, Md (9 ± 1.2 mm; P95 = 11 mm) and PMTA (106.5 ± 24.2 mm2 ; P95 = 150.8 mm2 ) were obtained. Correlation between PMTA and Md was positive (P < .001), and out-of-range values for Md and PMTA were similar (2.6% vs 5.3%); there was excellent agreement between both indexes (K = 0.82). CONCLUSIONS: Maximum diameter and PMTA are convenient indexes to describe PM dimensions. However, given the high equivalence between both indexes, we propose the use of Md due to its simplicity and ease of calculation. Our findings suggest that patients with any PM diameter ≥12 mm should be considered abnormal.

Válvula aórtica bicúspide: El prolapso y la calcificación valvular aórtica son marcadores de disfunción valvular significativa y de eventos cardiovasculares mayores a 5 años / Bicuspid Aortic Valve: Prolapse and Aortic Valve Calcification are Markers of Significant Valve Dysfunction and Major Cardiovascular Events at 5 Years

RESUMEN Introducción: La válvula aórtica bicúspide (VAB) es una cardiopatía congénita que puede asociarse a complicaciones aórticas y/o valvulares. Resulta importante identificar los grupos de riesgo para realizar un estrecho seguimiento e indicar la intervención a tiempo. Este trabajo propone analizar el impacto que tienen las características clínicas y morfológicas valvulares en el desarrollo de la disfunción valvular aórtica moderada/grave (significativa) y en la incidencia de eventos cardiovasculares mayores en adultos con VAB. Material y métodos: Se seleccionaron pacientes consecutivos con diagnóstico de VAB no sindromática (2010-2019) en seguimiento en el ICSI. Se recabó información clínica y ecocardiográfica de manera prospectiva. Se realizó análisis uni y multivariado para identificar las características clínicas y morfológicas predictoras de disfunción valvular significativa y de eventos cardiovasculares mayores (muerte, cirugía, síndrome aórtico). Una p menor a 0,05 fue considerada significativa. Resultados: Se siguieron 300 pacientes (44.3 ± 15.3 años, 71% varones). La mayoría con VAB tipo I y con presencia de rafe (79,6% y 77%, respectivamente). La edad media de diagnóstico fue de 36.3 ±16.2 años. Hubo 84 pacientes (31,2%) que presentaban disfunción valvular aórtica significativa al momento del inicio del estudio. Con un seguimiento de 4.9 ± 1.7 años, 23 pacientes requirieron cirugía cardíaca (7,7%) y 3 fallecieron (1%). Al final del seguimiento 101 pacientes (33,6%) presentaban disfunción valvular aórtica significativa. La presencia de al menos uno de los siguientes factores: prolapso valvular, calcificación valvular aórtica basal > 1 y edad > 50 años, se asoció a menor sobrevida libre de disfunción valvular aórtica significativa y de eventos mayores. Conclusiones: En nuestra cohorte, observamos una alta incidencia de eventos asociados a VAB. Dentro de las variables analizadas, la presencia de al menos un factor de riesgo se asoció a menor sobrevida libre de eventos mayores y disfunción significativa a 4.9 años.

ABSTRACT Background: Bicuspid aortic valve (BAV) is a congenital heart disease that can be associated with aortic and/or valve complications. It is important to identify risk groups for a closer follow up and timely intervention. Objective: The aim of this work is to analyze the impact of clinical and morphological valve characteristics in the development of moderate/severe (significant) aortic valve dysfunction and in the incidence of major cardiovascular events in adults with BAV. Methods: Consecutive patients with diagnosis of non-syndromic BAV (2010-2019) followed up at our institution were incorporated in the study. Clinical and echocardiographic information was prospectively collected. Univariate and multivariate analyses were performed to identify clinical and morphological characteristics that predict significant valve dysfunction and major cardiovascular events (death/surgery/aortic syndrome). A p value <0.05 was considered significant. Results: Three-hundred patients (44.3 ± 15.3 years, 71% men), the majority with type I BAV and presence of raphe (79.6% and 77%, respectively) were included. Mean age at diagnosis was 36.3±16.2 years, and 84 patients (31.2%) presented significant aortic valve dysfunction at the onset of the study. Twenty-three patients required cardiac surgery (7.7%) and 3 died (1%) during a follow-up of 4.9±1.7 years. At the end of the followup period, 101 (33.6%) patients had significant aortic valve dysfunction. The presence of at least 1 of the following factors: valve prolapse, baseline aortic valve calcification >1 and age >50 years were associated with lower significant aortic valve dysfunction and major cardiovascular event-free survival. Conclusions: In our cohort, we observed a high incidence of events associated with BAV. Among the variables analyzed, the presence of at least 1 risk factor was associated with lower event-free survival and significant dysfunction at 4.9 years.

Mecanismos de la disfunción y marcadores pronósticos en la válvula aórtica bicúspide / Mechanisms of Dysfunction and Prognostic Markers in Bicuspid Aortic Valve

RESUMEN Introducción: La complicación más frecuente de la válvula aórtica bicúspide (VAB) es la disfunción valvular aórtica, pero resulta complejo predecir qué pacientes desarrollarán estenosis aórtica (EAO) o insuficiencia aórtica (IAO) significativa (moderada/grave). Objetivos: Este trabajo busca analizar la progresión y las variables asociadas con el desarrollo de EAO e IAO significativa en adultos con VAB. Material y métodos: Se incluyeron pacientes consecutivos con VAB (2009-2017), se analizó la progresión de la disfunción valvular aórtica y en el grupo sin disfunción basal se identificaron variables predictoras de IAO y EAO significativas mediante análisis uni- y multivariados. Resultados: Se incluyeron 243 pacientes (43 ± 14,9 años, 73,2% hombres). La mayoría (n = 194, 79,8%) con VAB tipo I y rafe (n = 179; 73,6%). En el ecocardiograma basal, 111 pacientes presentaban IAO leve (45,6%); 49, moderada (20,1%); y 10, grave (4,1%). La EAO basal fue menos frecuente: 20 sujetos tuvieron EAO moderada (8,2%) y 12, EAO grave (4,9%). Hubo 2 muertes y 20 cirugías valvulares (8,2%) en 4,7 ± 1,7 años de seguimiento. Los pacientes con disfunción valvular significativa basal presentaron mayor tasa de progresión y requerimiento de cirugía valvular (p < 0,0001). Hubo 39 nuevos casos (17,2%) de IAO o EAO significativas en el seguimiento. El prolapso valvular aórtico(p < 0,001) y el sexo masculino (p < 0,04) se asociaron al desarrollo de IAO significativa (p < 0,001). El score de calcificación basal se asoció con EAO significativa (p < 0,02). Conclusiones: Los pacientes con VAB y disfunción valvular aórtica significativa basal requirieron cirugía en una elevada proporción a corto plazo. Se identificaron características clínicas y morfológicas asociadas con el desarrollo de disfunción valvular aórtica significativa.

ABSTRACT Introduction: The most common complication of the bicuspid aortic valve (BAV) is aortic valve dysfunction, but it is difficult to predict which patients will develop aortic stenosis (AS) or significant aortic regurgitation (AoR) (moderate/severe). Objectives: The aim of this work was to analyze the progression and the variables associated with the development of AS and significant AoR in adults with BAV. Methods: Consecutive patients with BAV were studied between 2009 and 2017. The progression of their aortic valve dysfunction was analyzed and in the group without baseline dysfunction, significant predictors of AoR and AS were identified through univariate and multivariate analysis. Results: Two hundred and forty-three patients (mean age 43±14.9 years, 73.2% men) were included in the study. The majority (n=194, 79.8%) with type I and raphe BAV (n=179, 73.6%). In the baseline echocardiogram, 111 patients presented mild (45.6%); 49, moderate (20.1%); and 10, severe (4.1%) AoR. Baseline AS was less frequent: 20 subjects had moderate (8.2%) and 12, severe (4.9%) AS. Two patients died and 20 valve surgeries (8.2%) were performed in 4.7±1.7 follow-up years. Patients with significant baseline valve dysfunction presented a higher rate of progression requiring valve surgery (p<0.0001). There were 39 new cases (17.2%) of significant AoR or AS at follow-up. Aortic valve prolapse (p<0.001) and male sex (p<0.04) were associated with the development of significant AoR (p<0.001). Baseline calcification score was associated with significant AS (p<0.02). Conclusions: A high proportion of patients with BAV and significant baseline aortic valve dysfunction required short-term surgery. Clinical and morphological characteristics associated with the development of significant aortic valve dysfunction were identified.

Effect of vascular endothelial growth factor gene transfer on infarct size, left ventricular function and myocardial perfusion in sheep after 2 months of coronary artery occlusion.

BACKGROUND: In large mammalian models of acute myocardial infarction (AMI), plasmid-mediated vascular endothelial growth factor (pVEGF) gene transfer has been shown to induce angio-arteriogenesis, proliferation of myocyte precursors and adult cardiomyocyte mitosis, reducing infarct size at 15 days after coronary artery occlusion. However, it is unknown whether these effects persist at longer follow-up times, nor how they affect cardiac performance. We thus assessed infarct size, left ventricular (LV) function and perfusion in 2-month-old ovine AMI. METHODS: Adult sheep with coronary artery occlusion were randomized to blindly receive ten intramyocardial injections of 3.8 mg of pVEGF or empty plasmid distributed at the infarct border. Three and 60 days later, LV perfusion (single-photon emission computed tomography) and function (stress echocardiography) were assessed. Finally, hemodynamics (LV catheterization), scar size and peri-infarct histology were studied. RESULTS: Infarct size was 30% smaller in pVEGF-treated sheep (23.6 ± 1.9% versus 32.7 ± 2.7% of the LV; p < 0.02). Percentage fractional shortening and wall thickening at the infarct border improved after pVEGF, as did myocardial perfusion and LV wall motion under pharmacological stress. Global LV function did not differ between groups, although the force-frequency response was preserved in pVEGF group and lost in placebo animals. These effects were associated with angio-arteriogenesis and proliferation of cardiomyocyte precursors. CONCLUSIONS: In sheep with AMI, pVEGF gene transfer affords long-term infarct size reduction, yielding regional LV function and perfusion improvement and reducing remodeling progression. These results suggest the potential usefulness of this approach in the clinical setting.

Reference values for echocardiographic parameters and indexes of left ventricular function in healthy, young adult sheep used in translational research: comparison with standardized values in humans.

Ovine models of ischemic heart disease and cardiac failure are increasingly used in translational research. However, reliable extrapolation of the results to the clinical setting requires knowing if ovine normal left ventricular (LV) function is comparable to that of humans. We thus assessed for echocardiographic LV dimensions and indexes in a large normal adult sheep population and compared them with standardized values in normal human adults. Bidimensional and tissue Doppler echocardiograms were performed in 69 young adult Corriedale sheep under light sedation. LV dimensions and indexes of systolic and diastolic function were measured. Absolute and body surface areanormalized values were compared to those for normal adult humans and their statistical distribution was assessed. Normalized dimensions (except for end diastolic diameter) as well as ejection fraction and fractional shortening fell within the ranges established by the American Society of Echocardiography and European Association of Echocardiography for normal adult humans. Normalized end diastolic diameter exceeded the upper normal limit but got close to it when correcting for the higher heart mass/body surface area ratio of sheep with respect to humans. Diastolic parameters also fell within normal human ranges except for a slightly lower mitral deceleration time. All values exhibited a Gaussian distribution. We conclude that echocardiographic parameters of systolic and diastolic LV performance in young adult sheep can be reliably extrapolated to the adult human, thus supporting the use of ovine models of human heart disease in translational research.

Expression of the MDR-1 gene-encoded P-glycoprotein in cardiomyocytes of conscious sheep undergoing acute myocardial ischemia followed by reperfusion.

We have recently reported that in chronic myocardial ischemia, adult mammalian cardiomyocytes express P-glycoprotein (P-gp). We now investigate if P-gp is also expressed in acute regional ischemia followed by reperfusion. Adult conscious sheep underwent 12-min occlusion of the mid-left anterior descending artery (inflatable cuff). Successful ischemia-reperfusion was confirmed by monitoring percent systolic left ventricular anterior wall thickening (sonomicrometry) during the whole ischemic period and every 10 min over 2 hr following cuff deflation. At 3, 24, and 48 hr after reperfusion, P-gp expression was investigated by immunohistochemistry and Western blot and MDR-1 mRNA by RT-PCR. Cardiomyocytes in the occluded artery territory (but not those in remote areas) consistently expressed P-gp at their sarcolemma. Whereas at 3 and 24 hr P-gp was mainly observed in the T tubules, at 48 hr it predominated in intercalated discs and gap junctions. RT-PCR and Western blot revealed higher expression in ischemic than in control myocardium. We conclude that in adult sheep with acute myocardial ischemia, the MDR-1 gene-encoded P-gp is expressed at the sarcolemma of the cardiomyocytes from 3 hr up to at least 48 hr after reperfusion.

Cardiomyocytes of chronically ischemic pig hearts express the MDR-1 gene-encoded P-glycoprotein.

The multidrug-resistant (MDR)-1 gene-encoded P-glycoprotein (Pgp-170) is not normally present in the cardiomyocyte. Given that in other tissues Pgp-170 is not found under normoxic conditions but is expressed during hypoxia, we searched for Pgp-170 in chronically ischemic porcine cardiomyocytes. Pgp-170 was detected and localized via immunohistochemistry in ischemic and nonischemic cardiomyocytes of eight adult pigs 8 weeks after placement of an Ameroid constrictor at the origin of the left circumflex artery (Cx). Regional myocardial ischemia in the Cx bed was documented with nuclear perfusion scans. Pgp-170 mass was quantified using Western blot analysis. In all pigs, Pgp-170 was consistently present in the sarcolemma and T invaginations of the cardiomyocytes of the ischemic zone. Pgp-170 expression decreased toward the border of the ischemic zone and was negative in nonischemic regions as well as in the myocardium of sham-operated animals. Western blot analysis yielded significantly higher Pgp-170 mass in ischemic than in nonischemic areas. We conclude that Pgp-170 is consistently expressed in the cardiomyocytes of chronically ischemic porcine myocardium. Its role in the ischemic heart as well as in conditions such as myocardial hibernation, stunning, and preconditioning may have potentially relevant clinical implications and merits further investigation.

Reducción del tamaño del infarto de miocardio mediante la transferencia génica de VEGF en ovejas / Myocardial infarct size reduction after VEGF gene transfer in sheep

La transferencia génica de plásmido codificante para VEGF (pVEGF) induce angiogénesis, incremento del índice mitótico e hiperplasia miocítica en cerdos con isquemia miocárdica crónica. El presente trabajo se realizó con el objetivo de estudiar el efecto del pVEGF sobre el tamaño del infarto de miocardio. Una hora después de la ligadura de la descendente anterior, 28 ovejas de 23 ± 0,5 kg se agruparon al azar para recibir 10 inyecciones intramiocárdicas de 3,8 mg de pVEGF (n = 14) o placebo (n= 14) distribuídas en la periferia del infarto. La función miocárdica se estudió con SPECT gatillado y los animales se sacrificaron 7, 10 y 15 días después del tratamiento. El tamaño del infarto fue el 34 por ciento menor en el grupo tratado que en el placebo (placebo: 17,1 ± 2,1 por ciento, VEGF: 11,2 ± 1,5 por ciento, p < 0,05) a los 15 pero no a los 10 días. Aunque hubo una leve tendencia a favor del grupo tratado, la mejoría de la función miocárdica no fue diferente entre grupos (placebo: 3,3 ± 1,4; VEGF: 3,8 ± 2,4; p = NS). El estudio histológico mostró que los mecanismos involucrados fueron la respuesta angiogénica a los 7 días (placebo: 676 ± 31 capilares / mm²: VEGF: 1925 ± 262; p <0,05), la menor fibrosis periinfarto a los 10 días (contenido de colágeno; placebo: 70, 1 ± 1,7 por ciento; VEGF: 43,5 ± 4,4 por ciento; p < 0,05); la proliferación de mioblastos a los 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días (proteína) posadministración. Conclusión: A los 15 días la transferencia génica de VEGF humano reduce el tamaño de infarto en ovejas mediante angiogénesis, disminución de la fibrosis e inducción de proliferación de mioblastos (miocardiogénesis).

Reducción del tamaño del infarto de miocardio mediante la transferencia génica de VEGF en ovejas / Myocardial infarct size reduction after VEGF gene transfer in sheep

La transferencia génica de plásmido codificante para VEGF (pVEGF) induce angiogénesis, incremento del índice mitótico e hiperplasia miocítica en cerdos con isquemia miocárdica crónica. El presente trabajo se realizó con el objetivo de estudiar el efecto del pVEGF sobre el tamaño del infarto de miocardio. Una hora después de la ligadura de la descendente anterior, 28 ovejas de 23 ± 0,5 kg se agruparon al azar para recibir 10 inyecciones intramiocárdicas de 3,8 mg de pVEGF (n = 14) o placebo (n= 14) distribuídas en la periferia del infarto. La función miocárdica se estudió con SPECT gatillado y los animales se sacrificaron 7, 10 y 15 días después del tratamiento. El tamaño del infarto fue el 34 por ciento menor en el grupo tratado que en el placebo (placebo: 17,1 ± 2,1 por ciento, VEGF: 11,2 ± 1,5 por ciento, p < 0,05) a los 15 pero no a los 10 días. Aunque hubo una leve tendencia a favor del grupo tratado, la mejoría de la función miocárdica no fue diferente entre grupos (placebo: 3,3 ± 1,4; VEGF: 3,8 ± 2,4; p = NS). El estudio histológico mostró que los mecanismos involucrados fueron la respuesta angiogénica a los 7 días (placebo: 676 ± 31 capilares / mm²: VEGF: 1925 ± 262; p <0,05), la menor fibrosis periinfarto a los 10 días (contenido de colágeno; placebo: 70, 1 ± 1,7 por ciento; VEGF: 43,5 ± 4,4 por ciento; p < 0,05); la proliferación de mioblastos a los 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días. La expresión del pVEGF fue positiva a los 3 (ARNm), 7 y 10 días (proteína) posadministración. Conclusión: A los 15 días la transferencia génica de VEGF humano reduce el tamaño de infarto en ovejas mediante angiogénesis, disminución de la fibrosis e inducción de proliferación de mioblastos (miocardiogénesis). (AU)